The present disclosure relates to methods for treating insulin resistance. In particular, the present disclosure relates to methods for treating, preventing, and/or reducing insulin resistance in a subject.
Insulin resistance is typically defined as failure of the cells of the body to respond to insulin. Inefficient insulin function affects skeletal muscle, liver and fat cells. The pancreas normally releases insulin after a meal to help transport glucose into the body's cells where the glucose is needed for energy production. Since cells must have glucose to survive, the body compensates by producing more insulin when a state of insulin resistance exists. This results in a high level of insulin in the blood (hyperinsulinemia) and high blood glucose (hyperglycemia) and consequent overstimulation of some tissues. Over time the relationship between glucose and insulin is not balanced and without treatment may lead to health complications. Hyperinsulinemia and insulin resistance affects levels of the body's lipids. Blood triglycerides and LDL (low-density lipoprotein, the “bad cholesterol”) go up while HDL (high-density lipoprotein, the “good cholesterol”) decreases. Changes in lipids can cause fatty plaque deposits to form in the vasculature and lead to cardiovascular disease and strokes.
Insulin resistance and metabolic syndrome are two terms often used interchangeably. Metabolic syndrome is essentially a subset of insulin resistance conditions, including obesity, alterations in lipid levels and abnormal glucose processing.
In one view, insulin resistance is not a disease per se or even a specific diagnosis but rather a set of pathological conditions that reflect this particular malfunction of the cells in the body. Insulin resistance is often associated with type II diabetes (T2D), obesity, stress, cardiovascular disease, hypertension, polycystic ovarian syndrome and nonalcoholic fatty liver disease. Most people with insulin resistance may not show any obvious symptoms for many years. If the body's insulin production fails to keep up with demand, then high blood sugar will occur. Once blood glucose reaches a high enough level, T2D is present. T2D is characterized by high blood sugar in the context of insulin resistance and insufficient insulin. The high glucose level can damage blood vessels in many organs, including the kidneys. Insulin resistance is a risk factor for developing T2D. It has also been postulated that there may be a link between insulin resistance and some types of cancer.
The cause and mechanism of insulin resistance are not fully understood. Genetic factors, lifestyle, and faulty signaling pathways have been implicated. There is not a single, or even a clearly defined set of genes responsible for the development of T2D. Insulin resistance can be viewed as an inflammatory disease with defective immune signaling. Many cytokines and chemokines are associated with this pathology. Examples include adiponectin, leptin, TNF alpha, interleukins IL-1 and IL-6, 3, 4-7, and the functions of the family of Toll-Like Receptors (TLR) such as TLR4, TLR7, and TLR9.
Various strategies are currently employed in the management of insulin resistance in T2D. Rates of T2D have increased markedly since 1960 in parallel with increasing obesity rates. Obesity is thought to be the primary cause of T2D in people who are genetically predisposed to the disease, except for people of East-Asian ancestry. In 2010, 285 million people were diagnosed with T2D compared to 30 million in 1985. T2D is typically a chronic disease associated with a 10 year shorter life expectancy. Long-term complications of high blood sugar include heart disease, ulcers of the skin, strokes, damaged eyesight, kidney failure, and poor blood flow in the limbs leading to amputations.
High blood sugar is only a symptom of T2D, not a cause. Modern therapies often target high glucose as the primary culprit of the disease. T2D is first managed by increasing physical exercise and dietary changes. If these measures do not sufficiently lower blood sugar, medications are employed. The most commonly used drug, insulin in various formulations, is used to lower blood glucose. Metformin, a biguanide drug, inhibits glucose production and release by the liver. By cutting off the glucose supply, metformin increases insulin sensitivity. Other therapies include insulin sensitizers, such as thiazolidinedione drugs Avandia and Actos, which lower blood glucose. They attach to the insulin receptors on cells in the body and cause the cells to become more responsive to insulin and remove more glucose from the blood. Insulin secretagogues increase insulin production and release by pancreas. The incretin-related drugs, glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors that disable degradation of GLP-1 also facilitate tissue uptake of glucose. Sodium-glucose co-transporter 2 (SGLT2) inhibitors increase glucose elimination in urine, and alpha-glucosidase inhibitors help limit degradation of glucose precursors in the gut.
Current treatments do not however reduce the incidence or effect cure. All present drugs have side effects that range from mild to life-threatening and these side effects frequently warrant FDA ‘Black Box’ warnings. One of the most common problems with T2D drugs is the induction of lactic acidosis (LA). LA occurs when too much lactic acid builds up in the body and can be fatal. Traditional therapies available to patients with type T2D after metformin failure, sulphonylureas and thiazolidinediones are often associated with weight gain, hypoglycemia or poor long-term efficacy.
No present T2D drugs address the progressive nature of disease and the underlying cause, insulin resistance. There is a need for agents with prolonged efficacy, disease modification, and improved safety.